Alzheimer’s Aβ42 and Aβ40 form mixed oligomers with direct molecular interactions

Gu, Lin; Guo, Zhefeng

doi:10.1016/j.bbrc.2020.11.092

Cited by 23 publications

(25 citation statements)

References 39 publications

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“…Whether A β 1–40 and A β 1-42 can co-fibrilise is still under debate, [95] found that mixing A β 1–40 and A β 1–42 leads to the generation of separate homomolecular fibrils. In contrast, studies have showed that mixing A β 1–40 and A β 1–42 leads to the formation of mixed oligomers and fibrils [29, 96]. However, it is accepted that A β 1–40 and A β 1–42 interact at the molecular level with increased levels of A β 1–40 inhibiting fibril formation and increased levels of A β 1–42 promoting aggregation [97–100].…”

Section: Discussionmentioning

confidence: 99%

Sticker-and-Linker Model for Amyloid Beta Condensation and Fibrillation

Connor

Quinn

Schaefer

2022

Preprint

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A major pathogenic hallmark of Alzheimer's disease is the presence of neurotoxic plaques composed of amyloid beta (Aβ) peptides in patients' brains. The pathway of plaque formation remains elusive, though some clues appear to lie in the dominant presence of Aβ1-42 in these plaques despite Aβ1-40 making up approximately 90% of the Aβ pool. We hypothesise that this asymmetry is driven by the hydrophobicity of the two extra amino acids that are incorporated in Aβ1-42. To investigate this hypothesis at the level of single molecules, we have developed a molecular 'sticker-and-linker lattice model' of unfolded Aβ. The model protein has a single sticker that may reversibly dimerise and elongate into semi-flexible linear oligomers. The growth is hampered by excluded-volume interactions that are encoded by the hydrophilic linkers but are rendered cooperative by the attractive interactions of hydrophobic linkers. For sufficiently strong hydrophobicity, the chains undergo liquid-liquid phase-separation (LLPS) into condensates that facilitate the nucleation of fibres. We find that a small fraction of Aβ1-40 in a mixture of Aβ1-40 and Aβ1-42 shift the critical concentration for LLPS to lower values. This study provides theoretical support for the hypothesis that LLPS condensates act as a precursor for aggregation and provides an explanation for the Aβ1-42-enrichment of aggregates in terms of hydrophobic interactions.

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Section: Discussionmentioning

confidence: 99%

Sticker-and-Linker Model for Amyloid Beta Condensation and Fibrillation

Connor

Quinn

Schaefer

2022

Preprint

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“…Another physical method, spin-label electron spin resonance (ESR) spectroscopy, has also been used as a spectroscopic ruler to locate the cross-β structure in inhomogeneous fibrils or oligomers and to explore the structural conversion and aggregation of proteins or peptides such as amyloid β-peptides, tau, transthyretin, and prion protein. [19][20][21][22][23][24][25][26][27][28] In this method, nitroxide spin-labels are introduced into the prion molecule, and one can measure the spin-spin interaction between two unpaired electrons at a distance within 20 Å using continuouswave ESR (CW-ESR) and 15 to 60 Å using double electron-electron resonance (DEER) ESR. 13,29,30 To investigate biomolecules with spin-labeled ESR, a nitroxide-based probe is attached through site-directed spin-labeling (SDSL) mutagenesis.…”

Section: Introductionmentioning

confidence: 99%

Location of the cross‐β structure in prion fibrils: A search by seeding and electron spin resonance spectroscopy

et al. 2022

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Prion diseases are transmissible fatal neurodegenerative disorders spreading between humans and other mammals. The pathogenic agent, prion, is a protease-resistant, β-sheet-rich protein aggregate, converted from a membrane protein called PrP C . PrP Sc is the misfolded form of PrP C and undergoes selfpropagation to form the infectious amyloids. Since the key hallmark of prion disease is amyloid formation, identifying and studying which segments are involved in the amyloid core can provide molecular details about prion diseases. It has been known that the prion protein could also form non-infectious fibrils in the presence of denaturants. In this study, we employed a combination of site-directed nitroxide spin-labeling, fibril seeding, and electron spin resonance (ESR) spectroscopy to identify the structure of the in vitro-prepared full-length mouse prion fibrils. It is shown that in the in vitro amyloidogenesis, the formation of the amyloid core is linked to an α-to-β structural transformation involving the segment 160-224, which contains strand 2, helix 2, and helix 3. This method is particularly suitable for examining the hetero-seeded amyloid fibril structure, as the unlabeled seeds are invisible by ESR spectroscopy.It can be applied to study the structures of different strains of infectious prions or other amyloid fibrils in the future.

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“…Among the various hypotheses for AD progression, the amyloid hypothesis has been a long-term adherent to the AD in the impairment of neuronal and cognitive functions, due to the formation of plaque in the brain by the accumulation of Aβ fragments and aggregates [2,3]. There are two main isoforms of the Aβ species (Aβ40 and Aβ42) that are the most abundant that appear in the brain [4]. Although Aβ40 is more abundant than Aβ42 in the brain [5,6], Aβ40 is present only in a subset of amyloid plaques, while Aβ42 is the main Aβ species in amyloid plaques, suggesting that the aggregation of Aβ42 may precede that of Aβ40 [4,7].…”

Section: Introductionmentioning

confidence: 99%

“…There are two main isoforms of the Aβ species (Aβ40 and Aβ42) that are the most abundant that appear in the brain [4]. Although Aβ40 is more abundant than Aβ42 in the brain [5,6], Aβ40 is present only in a subset of amyloid plaques, while Aβ42 is the main Aβ species in amyloid plaques, suggesting that the aggregation of Aβ42 may precede that of Aβ40 [4,7]. Although the structural difference between Aβ40 and Aβ42 is only two amino acid residues, Aβ42 exhibits a higher neurotoxicity than Aβ40 [8,9].…”

Section: Introductionmentioning

confidence: 99%

A Multi-Chamber Paper-Based Platform for the Detection of Amyloid β Oligomers 42 via Copper-Enhanced Gold Immunoblotting

Phan

Cho

2021

Biomolecules

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The early diagnosis of Alzheimer’s disease (AD) remains a challenge for medical scientists worldwide, leading to a number of research efforts that focus on biosensor development for AD biomarkers. However, the application of these complicated biosensors is limited in medical diagnosis, due to the difficulties in robust sensing platform development, high costs, and the necessity for technical professionals. We successfully developed a robust straightforward manufacturing process for the fabrication of multi-chamber paper devices using the wax printing method and exploited it to detect amyloid beta 42 oligomers (AβO42, a significant biomarker of AD) using copper-enhanced gold nanoprobe colorimetric immunoblotting. Small hydrophilic reaction chambers could concentrate the target sample to the desired size to improve the sensing performance. The copper-enhanced gold nanoprobe immunoblot using the designed multi-chamber platform exhibited a highly sensitive performance with a limit of detection of 320 pg/mL by the naked eye and 23.7 pg/mL by a smartphone camera. This process from sensing manufacture to sensing conduction is simple to perform whenever medical technicians require time- and cost-savings, without complicated instruments or the need for technical professionals, making it feasible to serve as a diagnostic tool worldwide for the early monitoring of AD and scalable devices for the sensing application of various biomarkers in clinical settings.

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Alzheimer’s Aβ42 and Aβ40 form mixed oligomers with direct molecular interactions

Cited by 23 publications

References 39 publications

Sticker-and-Linker Model for Amyloid Beta Condensation and Fibrillation

Sticker-and-Linker Model for Amyloid Beta Condensation and Fibrillation

Location of the cross‐β structure in prion fibrils: A search by seeding and electron spin resonance spectroscopy

A Multi-Chamber Paper-Based Platform for the Detection of Amyloid β Oligomers 42 via Copper-Enhanced Gold Immunoblotting

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